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Molecular mechanism of double Holliday junction dissolution.

Swuec P, Costa A - Cell Biosci (2014)

Bottom Line: Decatenation of double Holliday junctions, for example, is catalysed by two enzymes that work in tight coordination and belong to the same 'dissolvasome' complex.Within the dissolvasome, the RecQ-like BLM helicase provides the translocase function for Holliday junction migration, while the topoisomerase III alpha-RMI1 subcomplex works as a proficient DNA decatenase, together resulting in double-Holliday-junction unlinking.Here, we review the available architectural and biochemical knowledge on the dissolvasome machinery, with a focus on the structural interplay between its components.

View Article: PubMed Central - HTML - PubMed

Affiliation: Clare Hall laboratories, Cancer Research U.K. London Research Institute, London EN6 3LD, UK.

ABSTRACT
Processing of homologous recombination intermediates is tightly coordinated to ensure that chromosomal integrity is maintained and tumorigenesis avoided. Decatenation of double Holliday junctions, for example, is catalysed by two enzymes that work in tight coordination and belong to the same 'dissolvasome' complex. Within the dissolvasome, the RecQ-like BLM helicase provides the translocase function for Holliday junction migration, while the topoisomerase III alpha-RMI1 subcomplex works as a proficient DNA decatenase, together resulting in double-Holliday-junction unlinking. Here, we review the available architectural and biochemical knowledge on the dissolvasome machinery, with a focus on the structural interplay between its components.

No MeSH data available.


Related in: MedlinePlus

Structure of the dissolvasome enzymatic components. (A) Linear and three-dimensional structure of the human BLM helicase, in complex with a DNA and nucleotide substrate (PDB ID 4CGZ). (B) Linear and three-dimensional structure of human Topoisomerase IIIα (PDB ID 4CHT).
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Figure 1: Structure of the dissolvasome enzymatic components. (A) Linear and three-dimensional structure of the human BLM helicase, in complex with a DNA and nucleotide substrate (PDB ID 4CGZ). (B) Linear and three-dimensional structure of human Topoisomerase IIIα (PDB ID 4CHT).

Mentions: BLM (Sgs1 in yeast) provides the ATP-dependent motor function to convergently migrate a dHJ [15,16] and contains two separate domains (Figure 1A, [17]). The N-terminal region comprises a partially unstructured non-catalytic domain (NTD), which is the target of diverse post-translational modifications [18,19] and might contain a homo-oligomerisation module [20]. The BLM C-terminal domain contains the RecQ-like motor, belonging to the superfamily 2 of helicases, which are 3’ to 5’ single-stranded DNA translocases that can function as monomeric enzymes [21]. In RecQ proteins, a highly conserved helicase domain contains a bipartite active site for ATP binding and hydrolysis, where catalytic residues are contributed by two fused, neighbouring RecA-type modules [22]. The RecQ C-terminal (RQC) domain contains a zinc finger motif and a duplex-DNA binding Winged-Helix subdomain [22], which provides the proteinaceous pin to split the two DNA strands at the fork nexus (Figure 1A, PDB entry 4CGZ and [23]). Unexpectedly, a minimal helicase module containing the RecA sandwich and the zinc finger domain but lacking the Winged-Helix domain has been recently described, which can unwind a fork substrate in vitro[24]. Lastly, the Helicase and RNaseD C-terminal (HRDC) domain is a separate, globular entity that confers substrate specificity to BLM [25,26], being required for Holliday junction dissolution or unwinding, but not for the unwinding of a simple DNA-fork substrate [27].


Molecular mechanism of double Holliday junction dissolution.

Swuec P, Costa A - Cell Biosci (2014)

Structure of the dissolvasome enzymatic components. (A) Linear and three-dimensional structure of the human BLM helicase, in complex with a DNA and nucleotide substrate (PDB ID 4CGZ). (B) Linear and three-dimensional structure of human Topoisomerase IIIα (PDB ID 4CHT).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4109787&req=5

Figure 1: Structure of the dissolvasome enzymatic components. (A) Linear and three-dimensional structure of the human BLM helicase, in complex with a DNA and nucleotide substrate (PDB ID 4CGZ). (B) Linear and three-dimensional structure of human Topoisomerase IIIα (PDB ID 4CHT).
Mentions: BLM (Sgs1 in yeast) provides the ATP-dependent motor function to convergently migrate a dHJ [15,16] and contains two separate domains (Figure 1A, [17]). The N-terminal region comprises a partially unstructured non-catalytic domain (NTD), which is the target of diverse post-translational modifications [18,19] and might contain a homo-oligomerisation module [20]. The BLM C-terminal domain contains the RecQ-like motor, belonging to the superfamily 2 of helicases, which are 3’ to 5’ single-stranded DNA translocases that can function as monomeric enzymes [21]. In RecQ proteins, a highly conserved helicase domain contains a bipartite active site for ATP binding and hydrolysis, where catalytic residues are contributed by two fused, neighbouring RecA-type modules [22]. The RecQ C-terminal (RQC) domain contains a zinc finger motif and a duplex-DNA binding Winged-Helix subdomain [22], which provides the proteinaceous pin to split the two DNA strands at the fork nexus (Figure 1A, PDB entry 4CGZ and [23]). Unexpectedly, a minimal helicase module containing the RecA sandwich and the zinc finger domain but lacking the Winged-Helix domain has been recently described, which can unwind a fork substrate in vitro[24]. Lastly, the Helicase and RNaseD C-terminal (HRDC) domain is a separate, globular entity that confers substrate specificity to BLM [25,26], being required for Holliday junction dissolution or unwinding, but not for the unwinding of a simple DNA-fork substrate [27].

Bottom Line: Decatenation of double Holliday junctions, for example, is catalysed by two enzymes that work in tight coordination and belong to the same 'dissolvasome' complex.Within the dissolvasome, the RecQ-like BLM helicase provides the translocase function for Holliday junction migration, while the topoisomerase III alpha-RMI1 subcomplex works as a proficient DNA decatenase, together resulting in double-Holliday-junction unlinking.Here, we review the available architectural and biochemical knowledge on the dissolvasome machinery, with a focus on the structural interplay between its components.

View Article: PubMed Central - HTML - PubMed

Affiliation: Clare Hall laboratories, Cancer Research U.K. London Research Institute, London EN6 3LD, UK.

ABSTRACT
Processing of homologous recombination intermediates is tightly coordinated to ensure that chromosomal integrity is maintained and tumorigenesis avoided. Decatenation of double Holliday junctions, for example, is catalysed by two enzymes that work in tight coordination and belong to the same 'dissolvasome' complex. Within the dissolvasome, the RecQ-like BLM helicase provides the translocase function for Holliday junction migration, while the topoisomerase III alpha-RMI1 subcomplex works as a proficient DNA decatenase, together resulting in double-Holliday-junction unlinking. Here, we review the available architectural and biochemical knowledge on the dissolvasome machinery, with a focus on the structural interplay between its components.

No MeSH data available.


Related in: MedlinePlus